Blood disorders including leukemia and lymphoma can be cured with unrelated donor (URD) hematopoietic cell transplantation (HCT) and cord blood transplantation (CBT). Post-transplant complications and mortality may be lowered through comprehensive HLA matching of the stem cell source. KIR-HLA interactions further define transplant outcome. The clinical practice of URD HCT and CBT today has several unmet needs. HLA identity of the URD does not guarantee that the patient will not develop life-threatening post-transplant complications, indicating the presence of undetected MHC region variation. For patients who lack matched URDs, the rules that govern permissible HLA mismatches are needed so as to broaden the availability of HCT to all patients in need. In CBT, the relevance of undetected disparity at HLA-A, B, C, DR, and DQ is unknown. Natural killer (NK)-mediated effects may further modulate transplant risks. Overall, clinical outcome is inferior for patients of non-Caucasian ethnicity. This project has two major goals. First, we will define the clinical importance of MHC residue variation after URD HCT and CBT by measuring the impact of HLA mismatching in non-Caucasian populations, identifying non-permissible HLA mismatches, and novel MHC resident genes. Second, we will define the clinical impact of KIR-HLA interactions, determine the molecular mechanisms underlying donor NK alloreactivity through a systematic evaluation of activating KIRs and haplotypes, and define mechanisms involved for the development of NK alloreactivity. These research questions will address the current roadblocks in URD HCT and CBT and provide novel laboratory-based information that can be translated to clinical practice for all patients of diverse racial background.